US4348332A - Phosphonoformaldehyde, a process for its preparation and its use as an intermediate product for the preparation of medicaments - Google Patents

Phosphonoformaldehyde, a process for its preparation and its use as an intermediate product for the preparation of medicaments Download PDF

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US4348332A
US4348332A US06/308,717 US30871781A US4348332A US 4348332 A US4348332 A US 4348332A US 30871781 A US30871781 A US 30871781A US 4348332 A US4348332 A US 4348332A
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acid
phosphonoformaldehyde
salt
preparation
formula
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US06/308,717
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Hermann Oediger
Folker Lieb
Hans Disselnkotter
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Bayer AG
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07F—ACYCLIC, CARBOCYCLIC OR HETEROCYCLIC COMPOUNDS CONTAINING ELEMENTS OTHER THAN CARBON, HYDROGEN, HALOGEN, OXYGEN, NITROGEN, SULFUR, SELENIUM OR TELLURIUM
    • C07F9/00—Compounds containing elements of Groups 5 or 15 of the Periodic System
    • C07F9/02—Phosphorus compounds
    • C07F9/28—Phosphorus compounds with one or more P—C bonds
    • C07F9/38—Phosphonic acids RP(=O)(OH)2; Thiophosphonic acids, i.e. RP(=X)(XH)2 (X = S, Se)
    • C07F9/3804—Phosphonic acids RP(=O)(OH)2; Thiophosphonic acids, i.e. RP(=X)(XH)2 (X = S, Se) not used, see subgroups
    • C07F9/3886—Acids containing the structure -C(=X)-P(=X)(XH)2 or NC-P(=X)(XH)2, (X = O, S, Se)
    • C07F9/3891—Acids containing the structure -C(=X)-P(=X)(XH)2, (X = O, S, Se)
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07F—ACYCLIC, CARBOCYCLIC OR HETEROCYCLIC COMPOUNDS CONTAINING ELEMENTS OTHER THAN CARBON, HYDROGEN, HALOGEN, OXYGEN, NITROGEN, SULFUR, SELENIUM OR TELLURIUM
    • C07F9/00—Compounds containing elements of Groups 5 or 15 of the Periodic System
    • C07F9/02—Phosphorus compounds
    • C07F9/28—Phosphorus compounds with one or more P—C bonds
    • C07F9/38—Phosphonic acids RP(=O)(OH)2; Thiophosphonic acids, i.e. RP(=X)(XH)2 (X = S, Se)
    • C07F9/3804—Phosphonic acids RP(=O)(OH)2; Thiophosphonic acids, i.e. RP(=X)(XH)2 (X = S, Se) not used, see subgroups
    • C07F9/3808—Acyclic saturated acids which can have further substituents on alkyl

Definitions

  • the present invention relates to a certain new phosphorus compound and to an unobvious process for its production.
  • the compound can be used as an intermediate product for the synthesis of pharmaceuticals.
  • the compound of the invention finds particular use in the synthesis of an antiviral agent for use in medicine.
  • Both radicals R represent an alkyl group with 1 to 4 carbon atoms, is warmed with water and, if it is desired to convert the free phosphonoformaldehyde into a salt thereof, is then reacted with a base.
  • the phosphonoformaldehyde according to the invention can subsequently be converted into salts by conventional methods.
  • dialkoxymethanephosphonic acids used as starting substances for the process according to the invention are known (see Bull. Chem. Soc. Japan 51 (1978), 2169), or they can be prepared by known processes.
  • the two radicals R preferably represent, as the alkyl group with 1 to 4 carbon atoms, a methyl or ethyl group.
  • Compounds of formula (II) which may be mentioned are, for example, dimethoxymethanephosphonic acid, diethoxymethanephosphonic acid and dipropoxymethanephosphonic acid.
  • trimethylsilyl esters used, but it is sufficient for the trimethylsilyl esters such as are formed when dialkoxymethanephosphonic acid dialkyl esters are reacted with for example, trimethylbromosilane to be hydrolysed, without further purification.
  • the process is thus particularly economical.
  • the reaction time depends on the temperature and on the structure of the radical R, and is generally between 1 hour and 3 hours.
  • the resulting compound of formula (I) can be isolated either by evaporating the solution or, for isolation in the form of a phosphonic acid salt, after adding to the solution an amount of an inorganic or organic base, for example an inorganic base such as an alkali metal hydroxide, which is sufficient for neutralisation of the solution, for example by adding aqueous sodium hydroxide solution.
  • an inorganic base such as an alkali metal hydroxide
  • Suitable organic bases are, for example, pyridine and triethylamine.
  • aldehyde acetals into the free aldehydes with strong acids, for example hydrochloric acid, sulphuric acid or phosphoric acid.
  • strong acids for example hydrochloric acid, sulphuric acid or phosphoric acid.
  • acid and elevated temperatures are required (see Vogel, Text-Book of Organic Chemistry, 3rd Edition, Page 323, Longmans, London).
  • the process can be carried out as a one-pot reaction, starting from the dialkoxymethanephosphonic acid alkyl ester, in a particularly economical manner if the stoichiometrically required amount of, for example, trimethylbromosilane is used to prepare the starting compound of the general formula (II).
  • Phosphonoformaldehyde is an intermediate product for the preparation of medicaments, in particular for the preparation of phosphonohydroxyacetic acid, which has antiviral properties.
  • phosphonoformaldehyde for formula (I) in the form of its sodium salt reacts with hydrocyanic acid to give the new compound phosphonohydroxyacetonitrile of formula (III), which can be converted into phosphonohydroxyacetic acid of formula (IV) by hydrolysis of the nitrile group, for example with hydrochloric acid.
  • Phosphonohydroxyacetic acid has an action against herpes viruses in warm-blooded animals, in particular against type I and II herpes simplex viruses.
  • the evaporation residue was dissolved in 600 ml of water, hexamethyldisiloxane and methanol were then distilled off at a temperature rising to about +80° C., the water which was also distilled off being continuously replaced, and the mixture was then stirred for a further hour at 80° to 85° C.
  • the mixture was cooled, adjusted to a pH value of about 7.5 with 3 N NaOH and evaporated in vacuo and the crystalline residue was dried in vacuo.
  • Phosphonoformaldehyde can be converted into phosphonohydroxyacetic acid in the following manner:

Abstract

The invention relates to phosphonoformaldehyde of the formula ##STR1## Also included in the invention is a method for the manufacture of said phosphonoformaldehyde in which a dialkoxymethane phosphonic acid is warmed with water (then reacted with a base if a salt is desired). Phosphonoformaldehyde is an intermediate for the manufactureof phosphonohydroxy acetic acid, which is an antiviral agent.

Description

The present invention relates to a certain new phosphorus compound and to an unobvious process for its production. The compound can be used as an intermediate product for the synthesis of pharmaceuticals.
Formylphosphonic acid esters have already been disclosed (see U.S. Pat. No. 3,784,590). However, as investigations carried out by the applicants have shown, they are very unstable and are therefore not particularly suitable as intermediate products for industrial syntheses.
Dimethoxymethanephosphonic acid in the form of the monoanilinium salt has also been disclosed (see Bull. Chem. Soc. Japan 51 (1978), 2169)
According to the present invention there is provided the compound phosphonoformaldehyde of the formula ##STR2## or a salt thereof.
The compound of the invention finds particular use in the synthesis of an antiviral agent for use in medicine.
According to the present invention there is further provided a process for the production of a compound of the invention in which a dialkoxymethanephosphonic acid of the formula ##STR3## in which
Both radicals R represent an alkyl group with 1 to 4 carbon atoms, is warmed with water and, if it is desired to convert the free phosphonoformaldehyde into a salt thereof, is then reacted with a base.
The phosphonoformaldehyde according to the invention can subsequently be converted into salts by conventional methods.
If, in the reaction, dimethoxymethanephosphonic acid is used as the starting substance and sodium hydroxide solution is used for the neutralisation, the course of the reaction is illustrated by the following equation: ##STR4##
The dialkoxymethanephosphonic acids used as starting substances for the process according to the invention are known (see Bull. Chem. Soc. Japan 51 (1978), 2169), or they can be prepared by known processes.
In the formula (II), the two radicals R preferably represent, as the alkyl group with 1 to 4 carbon atoms, a methyl or ethyl group.
Compounds of formula (II) which may be mentioned are, for example, dimethoxymethanephosphonic acid, diethoxymethanephosphonic acid and dipropoxymethanephosphonic acid.
It is not necessary to add the starting materials as such. It is sufficient to use aqueous solutions of these compounds, such as are formed in situ when the corresponding trimethylsilyl esters are hydrolysed with water.
Moreover, it is also not necessary to purify the trimethylsilyl esters used, but it is sufficient for the trimethylsilyl esters such as are formed when dialkoxymethanephosphonic acid dialkyl esters are reacted with for example, trimethylbromosilane to be hydrolysed, without further purification. The process is thus particularly economical.
When warming the compounds of the formula (II) in water in order to carry out the process according to the present invention generally a temperature in the range from +70° to +100° C., preferably between +80° and +90° C., is used.
The reaction time depends on the temperature and on the structure of the radical R, and is generally between 1 hour and 3 hours.
The resulting compound of formula (I) can be isolated either by evaporating the solution or, for isolation in the form of a phosphonic acid salt, after adding to the solution an amount of an inorganic or organic base, for example an inorganic base such as an alkali metal hydroxide, which is sufficient for neutralisation of the solution, for example by adding aqueous sodium hydroxide solution. Suitable organic bases are, for example, pyridine and triethylamine.
It is indeed known to convert aldehyde acetals into the free aldehydes with strong acids, for example hydrochloric acid, sulphuric acid or phosphoric acid. For this conversion, for example in the case of aliphatic aldehyde acetals, relatively large amounts of acid and elevated temperatures are required (see Vogel, Text-Book of Organic Chemistry, 3rd Edition, Page 323, Longmans, London).
However, it is to be described as surprising that the acidity of the compounds of formula (II) is sufficient to prepare the compound of formula (I), which is in the form of the hydrate and is therefore unusually stable, without the addition of foreign acids.
It is exceptionally advantageous that the addition of foreign acids can be dispensed with, since isolation of the aldehyde, for example as the phosphonic acid salt, is thus particularly simple.
The process can be carried out as a one-pot reaction, starting from the dialkoxymethanephosphonic acid alkyl ester, in a particularly economical manner if the stoichiometrically required amount of, for example, trimethylbromosilane is used to prepare the starting compound of the general formula (II).
Phosphonoformaldehyde is an intermediate product for the preparation of medicaments, in particular for the preparation of phosphonohydroxyacetic acid, which has antiviral properties.
For example, phosphonoformaldehyde for formula (I) in the form of its sodium salt reacts with hydrocyanic acid to give the new compound phosphonohydroxyacetonitrile of formula (III), which can be converted into phosphonohydroxyacetic acid of formula (IV) by hydrolysis of the nitrile group, for example with hydrochloric acid. ##STR5##
Phosphonohydroxyacetic acid has an action against herpes viruses in warm-blooded animals, in particular against type I and II herpes simplex viruses.
The process for the production of phosphonohydroxyacetonitrile according to the present invention is illustrated by the following Examples.
EXAMPLE 1 Na2 salt of phosphonoformaldehyde
184 g (1 mole) of dimethoxymethanephosphonic acid dimethyl ester were dissolved in 800 ml of acetonitrile, 366 g (2.4 moles) of trimethylbromosilane were added at +15° to +20° C. and the mixture was then stirred at +40° to +45° C. for 2 hours. The solvent and the excess trimethylbromosilane were removed at +30° to +40° C. in vacuo, the evaporation residue was dissolved in 600 ml of water, hexamethyldisiloxane and methanol were then distilled off at a temperature rising to about +80° C., the water which was also distilled off being continuously replaced, and the mixture was then stirred for a further hour at 80° to 85° C. The mixture was cooled, adjusted to a pH value of about 7.5 with 3 N NaOH and evaporated in vacuo and the crystalline residue was dried in vacuo.
170 g (89% of theory) of the dihydrate of the Na2 salt of phosphonoformaldehyde were obtained in this manner.
1 H-NMR: δ=4.9 (1H, d, J=4.0 Hz) ppm (D2 O)
13 C-NMR: δ=90 (d, JC,P =180.7 Hz) ppm (D2 O)
Phosphonoformaldehyde can be converted into phosphonohydroxyacetic acid in the following manner:
(a) The Na2 salt of phosphonohydroxyacetonitrile
15 g (0.083 mole) of the dihydrate of the Na2 salt of phosphonoformaldehyde were suspended in 30 ml of H2 O, and 10 ml of anhydrous hydrocyanic acid were then added at about +25° C. The temperature rose to +30° C.; a clear solution was formed. The mixture was kept for a further hour at +30° C., the excess hydrocyanic acid and the water were then removed in vacuo and the residue was dried in vacuo.
15 g (95% of theory) of the dihydrate of the Na2 salt of phosphonohydroxyacetonitrile were obtained in this manner.
1 H-NMR: δ=4,5 (1H, d,J=16,0 Hz) ppm (D2 O)
13 C-NMR: δ=122.3 (C.tbd.N); 60.2 (d, JC,P =133.3 Hz) ppm (D2 O)
(b) The Na3 salt of phosphonohydroxyacetic acid
9.5 g (0.05 mole) of the dihydrate of the Na2 salt of phosphonohydroxyacetonitrile were converted into phosphonohydroxyacetonitrile on an acid ion exchanger, the phosphonohydroxyacetonitrile was dissolved in 30 ml of concentrated hydrochloric acid and the solution was left to stand overnight. It was warmed for a further 4 hours to 85° to 90° C., the solvent was removed in vacuo, the evaporation residue was taken up in water and the solution was filtered over an acid ion exchanger. The filtrate was evaporated in vacuo, the solution obtained by dilution with water was adjusted to a pH value of about 7.5 and the water was removed in vacuo. 8.3 g (75% of theory) of the Na3 salt of phosphonohydroxyacetic acid were obtained in this manner.
1 H-NMR: δ=4.1 (1H, d, J=18 Hz) ppm (D2 O)
13 C-NMR: δ=168.1 (COO.sup.θ); 73.7 (d, JC,P =134.1) ppm (D2 O)
EXAMPLE 2
306 g (2 moles) of trimethylbromosilane were added to 184 g (1 mole) of dimethoxymethanephosphonic acid dimethyl ester of +15° to +20° C. and the mixture was then stirred at +40° to +45° C. for 2 hours. 600 ml of water were then added at +10° to +20° C. and the procedure followed was as described in Example 1. 173 g (91% of theory) of the dihydrate of the Na2 salt of phosphonoformaldehyde were obtained.
EXAMPLE 3
12.0 g (0.05 mole) of diethoxymethanephosphonic acid diethyl ester were dissolved in 40 ml of acetonitrile, 18.3 g (0.12 mole) of trimethylbromosilane were added at +15° to +20° C. and the mixture was then stirred at +45° to +50° C. for 2 hours. The procedure followed was then as described in Example 1, but the mixture was adjusted to a pH value of about 7.5 with 2 N LiOH. 6.3 g (90% of theory) of the hydrate of the Li2 salt of phosphonoformaldehyde were obtained in this manner.
EXAMPLE 4
9.2 g (0.05 mole) of dimethoxymethanephosphonic acid dimethyl ester were dissolved in 40 ml of acetonitrile, 18.3 g (0.12 mole) of trimethylbromosilane were added to +15° to +20° C. and the mixture was then stirred at +45° to +50° C. for two hours. The procedure followed was then as described in Example 1, but one equivalent of pyridine was added. 9.3 g (90% of theory) of the hydrate of the monopyridinium salt of phosphonoformaldehyde were obtained in this manner.
Melting point: 156° to 158° C. (decomposition).

Claims (1)

What is claimed is:
1. A compound which is phosphonoformaldehyde of the formula ##STR6## or a salt thereof.
US06/308,717 1980-10-23 1981-10-05 Phosphonoformaldehyde, a process for its preparation and its use as an intermediate product for the preparation of medicaments Expired - Fee Related US4348332A (en)

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DE19803039998 DE3039998A1 (en) 1980-10-23 1980-10-23 PHOSPHONOFORMALDEHYDE, A METHOD FOR THE PRODUCTION THEREOF AND ITS USE AS AN INTERMEDIATE PRODUCT FOR THE PRODUCTION OF MEDICINAL PRODUCTS

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Cited By (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US5578190A (en) * 1984-12-28 1996-11-26 Monsanto Company Process for the preparation of glyphosate and glyphosate derivatives
USRE35389E (en) * 1985-09-11 1996-12-03 Hoechst Aktiengesellschaft Process for the preparation of N-phosphonomethylglycine
US6054608A (en) * 1997-05-05 2000-04-25 Monsanto Company Method for preparing formylphosphonic acid
US6274760B1 (en) 2000-03-14 2001-08-14 Monsanto Co. Preparation of formylphosphonic acid from tertiary aminomethylphosphonic acid N-oxides
US6441223B1 (en) 2000-11-30 2002-08-27 Monsanto Technology Llc Method of making phosphorus-containing compounds and products thereof

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US2900408A (en) * 1956-05-08 1959-08-18 Henkel & Cie Gmbh Acid esters of acyl-phosphorous acids and method of making the same
US3032500A (en) * 1959-12-31 1962-05-01 American Cyanamid Co Sequestration of metal ions
US3784590A (en) * 1969-01-02 1974-01-08 Merck & Co Inc Hydroxy and imino containing phosphonic acid diesters

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US4339443A (en) * 1978-09-22 1982-07-13 Fbc Limited Compounds and compositions
DE2941384A1 (en) * 1979-10-12 1981-04-23 Bayer Ag, 5090 Leverkusen PHOSPHONO-HYDROXY-ACETIC ACID, METHOD FOR THE PRODUCTION THEREOF AND THEIR USE AS MEDICINAL PRODUCTS

Patent Citations (3)

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Publication number Priority date Publication date Assignee Title
US2900408A (en) * 1956-05-08 1959-08-18 Henkel & Cie Gmbh Acid esters of acyl-phosphorous acids and method of making the same
US3032500A (en) * 1959-12-31 1962-05-01 American Cyanamid Co Sequestration of metal ions
US3784590A (en) * 1969-01-02 1974-01-08 Merck & Co Inc Hydroxy and imino containing phosphonic acid diesters

Non-Patent Citations (5)

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Title
Ackerman et al., "J. Am. Chem. Soc.", vol. 78 (1956), pp. 4444-4447. *
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Cited By (11)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US5578190A (en) * 1984-12-28 1996-11-26 Monsanto Company Process for the preparation of glyphosate and glyphosate derivatives
USRE35389E (en) * 1985-09-11 1996-12-03 Hoechst Aktiengesellschaft Process for the preparation of N-phosphonomethylglycine
US6054608A (en) * 1997-05-05 2000-04-25 Monsanto Company Method for preparing formylphosphonic acid
US6762317B2 (en) 1997-05-05 2004-07-13 Monsanto Company Method for preparing formylphosphonic acid
US20040225147A1 (en) * 1997-05-05 2004-11-11 Monsanto Company Method for preparing formylphosphonic acid
US7091376B2 (en) 1997-05-05 2006-08-15 Monsanto Technology Llc Method for preparing formylphosphonic acid
US7294733B2 (en) 1997-05-05 2007-11-13 Monsanto Technology Llc Method for preparing formylphosphonic acid
US6274760B1 (en) 2000-03-14 2001-08-14 Monsanto Co. Preparation of formylphosphonic acid from tertiary aminomethylphosphonic acid N-oxides
US6441223B1 (en) 2000-11-30 2002-08-27 Monsanto Technology Llc Method of making phosphorus-containing compounds and products thereof
US20030078446A1 (en) * 2000-11-30 2003-04-24 Monsanto Technology Llc Method of making phosphorus-containing compounds and products thereof
US6864218B2 (en) 2000-11-30 2005-03-08 Monsanto Technology Llc Method of making phosphorus-containing compounds and products thereof

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JPS5795995A (en) 1982-06-15
CA1187895A (en) 1985-05-28
DE3039998A1 (en) 1982-06-03
US4447367A (en) 1984-05-08
FI813290L (en) 1982-04-24
AU7674781A (en) 1982-04-29
DK467581A (en) 1982-04-24
FI69081C (en) 1985-12-10
EP0050778B1 (en) 1984-06-20
EP0050778A1 (en) 1982-05-05
JPH0148914B2 (en) 1989-10-20
NO813398L (en) 1982-04-26
ATE8052T1 (en) 1984-07-15
FI69081B (en) 1985-08-30
ES506461A0 (en) 1982-08-16
DE3164330D1 (en) 1984-07-26

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